Method for producing substituted nitro benzoic acids by oxidation of corresponding nitro toluenes, nitrol benzyl alcohols, esters and/or ethers

ABSTRACT

The present invention relates to the preparation of nitrobenzoic acids by oxidizing particular nitrotoluenes, nitrobenzyl alcohols, esters and/or ethers in the presence of nitric acid at elevated temperature and elevated pressure. It has been found that the particular nitrotoluenes, nitrobenzyl alcohols, esters and/or ethers may be oxidized particularly reliably and in high yields using nitric acid to the benzoic acid derivatives when they are metered into the nitric acid.

[0001] The present invention relates to a process for preparingspecifically substituted nitrobenzoic acids by oxidizing thecorresponding nitrotoluenes, nitrobenzyl alcohols, and esters and/orethers thereof using nitric acid.

[0002] Substituted nitrobenzoic acids are interesting intermediates foractive pharmaceutical and agrochemical ingredients.

[0003] Nitrotoluenes having additional electron-withdrawing, especiallyoxygen-containing, substituents are compounds whose autothermaldecomposition leads to a considerable release of energy. In view of thehigh reaction temperatures which are required at the same time, theoxidation of such compounds is difficult to realize from a safety pointof view. When carried out on an industrial scale, it requiresconsiderable control, and special measures have to be taken to minimizethe safety risk.

[0004] Commercially, electron-deficient nitrotoluenes are oxidized usingnitric acid in continuously operated delay tubes, as described in theChemiker-Zeitung 104 (1980), p. 349-351. A mixture of nitric acid andtoluene is preheated and pumped under high pressure through a verticalreactor tube. It is pointed out that there is always a risk of anexplosion here, for which reason a protective wall is always constructedbetween the reactor and the control room and the reaction may only becarried out by remote control from the control room.

[0005] A further disadvantage of such a continuous process is thatstart-up and shut-down conditions may lead to off-spec material, whichis problematic especially in products having relatively low tonnages.

[0006] GB-A-705 195 describes the oxidation of toluenesulfonic acids andnitrotoluenesulfonic acids using nitric acid at 120-300° C. in anautoclave, optionally with the aid of oxygen, nitrous gases, metalnitrates or metal nitrites. The components are added together and thepressure reactor is heated until a strongly exothermic reactioncommences. Both continuous and semicontinuous performance of thereaction are described. In the semicontinuous procedure, the oxidizingagent is metered into the (nitro)toluenesulfonic acid.

[0007] DE-A-197 49 723 describes the preparation of4-nitro-2-sulfonylbenzoic acid by oxidizing 4-nitrotoluene-2-sulfonicacid at 120-170° C. and a pressure of up to 12 bar by initially chargingthe toluene dissolved in water and metering in the nitric acid. Explicitreference is made to the safety aspects of this reaction. In addition,the yields of 75-85% achievable in this process are unsatisfactory withregard to industrial preparation.

[0008] The object of the present invention is accordingly to provide anoxidation process by which substituted nitrobenzoic acids may beobtained without safety risk and in high reproducible yields even insmall tonnages.

[0009] Surprisingly, it has been found that this object may be achievedby a semibatch process involving initially charging the oxidizing agentand then metering in the reactant in the form of a nitrotoluene,nitrobenzyl alcohol, ester and/or ether at elevated temperature andelevated pressure.

[0010] The invention accordingly provides a process for preparingnitrobenzoic acids of the general formula (I)

[0011] where

[0012] each X is independently nitro, cyano, sulfonyl, carboxyl,carbonylphenyl, trifluoromethyl or trichloromethyl,

[0013] each Y is independently phenyl, fluorine, chlorine, bromine oriodine and the phenyl radical may in turn be substituted by up to 3 Xand/or Y radicals other than hydrogen,

[0014] m has the value 0, 1, 2 or 3 and

[0015] n has the value 0, 1, 2 or 3,

[0016] and the sum of m and n has the value 0, 1, 2, 3 or 4,

[0017] from compounds of the general formula (II)

[0018] where

[0019] X, Y, m, n and also the sum of n and m are each as defined abovefor the general formula (I) and

[0020] R is H or an OR′ radical and

[0021] R′ is H, straight-chain or branched C₁-C₁₀-alkyl orstraight-chain or branched C₁-C₁₀-carbonylalkyl or R′ is a radical ofthe general formula (III)

[0022]  or a radical of the general formula (IV),

[0023]  where X, Y, n, m and also the sum of n and m are each as definedfor the general formula (I),

[0024] characterized in that a mixture of nitric acid and water isheated at a pressure in the range of 2-20 bar at temperatures in therange of 100-220° C. and the compound of the general formula (II) ismetered into this heated mixture of nitric acid and water,

[0025] although compounds of the general formula (II) exclude2-halo-6-nitrobenzyl alcohols, esters and ethers of the general formula(V) and

[0026]  where

[0027] R′ is as defined for the general formula (II),

[0028] R¹, R² and R³ are each independently H, fluorine, chlorine,bromine, nitro or carboxyl and

[0029] Hal is fluorine, chlorine or bromine.

[0030] A decisive factor in the process according to the invention isthe mixing of the reactant and the nitric acid in such a manner that thenitric acid is initially charged and heated in a mixture with water andthe reactant to be oxidized is then metered in. The steady stateconcentration of the reactant, whose decomposition temperature isfrequently close to the range in which the heat development of thedesired reaction takes place, is thus maintained at a particularly lowlevel in the reaction mixture. As soon as the reactant reaches thenitric acid reaction mixture, it reacts immediately with the nitric acidto give an unreactive product. The maximum reactant concentrations inthe reaction mixture in the process according to the invention are 7% byweight, preferably 6% by weight and in particular 5% by weight. In thismanner, the danger potential of the oxidation is quite decisivelyreduced.

[0031] In the general formulae (I) and (II), each X is independently andpreferably a sulfonic acid or nitro radical and each Y is independentlyand preferably fluorine or chlorine. The index n preferably has a valueof 0, 1 or 2 and the index m likewise preferably has a value of 0, 1 or2, and the sum of n and m preferably has the value 1 or 2. Preferably, ahydrogen atom or a fluorine atom, preferably a hydrogen atom, is in oneof the o-positions to the group —CH₂R to be oxidized.

[0032] Preference is given to applying the process according to theinvention to those compounds of the general formula (II) which have amarked tendency to thermally decompose. Particular preference is givento using nitrotoluenes and in particular nitrotoluenesulfonic acids asreactants. Very particular preference is given to oxidizing4-nitrotoluene-2-sulfonic acid to 4-nitro-2-sulfonylbenzoic acid.

[0033] The process according to the invention is carried out at apressure of 2-20 bar, preferably of 4-15 bar, more preferably of 6-12bar and in particular of 10-12 bar. Since nitrogen oxides are releasedin the course of the reaction, it is sensible to control the pressurevia a pressure-retaining valve and to allow the nitrogen oxides toescape to the required extent.

[0034] The temperature at which the process according to the inventionis carried out is in the range of 100-220° C., preferably of 120-200° C.and more preferably of 140-180° C.

[0035] The reaction is carried out using an initial charge of 10-90%,and preferably 20-65%, nitric acid.

[0036] The molar ratio of the compound of the general formula (II) tonitric acid is in the range of (2-20):1, preferably in the range of(3-10):1 and more preferably in the range of (4-8):1.

[0037] The process according to the invention is customarily carried outin such a manner that the nitric acid is initially charged into apressure reactor and heated. The reactant solution or melt is thenmetered in within 1-48, preferably 2-24 and more preferably 4-12, hours.The completed metering in is optionally followed by a certain continuedreaction time at the reaction temperature for the purposes of completingthe conversion. This continued reaction time is customarily in the rangeof 1-15 hours and preferably in the range of 3-8 hours.

[0038] After the end of the oxidation and expiry of any continuedstirring time, the reaction mixture may be cooled, the reaction vesseldepressurized and the remaining nitrogen oxides blown out, for exampleusing nitrogen.

[0039] The nitrosulfonylbenzoic acids of the general formula (I)prepared according to the invention may be isolated, for example, byadding an aqueous, preferably saturated, potassium chloride solution andfiltering off the monohydrate of the potassium salt ofnitrosulfonylbenzoic acid which then precipitates. After it has dried, aproduct is generally obtained which has a purity of over 95% by weight(determined by HPLC).

[0040] The potassium salt may also be precipitated in such a manner thatan aqueous potassium hydroxide solution, for example having aconcentration of 30-50% by weight, is added until the pH is in the rangeof, for example, 0.5-2.5. The majority of the nitrosulfonylbenzoic acidthen precipitates as the potassium salt. If necessary, the precipitationmay be completed by adding an aqueous, preferably saturated, potassiumchloride solution.

[0041] Other methods for isolating the benzoic acid derivatives of thegeneral formula (I) obtained by oxidation are generally known to thoseskilled in the art.

[0042] In a particular embodiment of the process according to theinvention, 10-90%, preferably 20-50%, of the nitric acid to be used isinitially charged and heated, and the reactant and remaining nitric acidare then metered into the reactor simultaneously but separately.

[0043] It may also be advantageous to add substances to the initiallycharged nitric acid which release or contain NO_(x), for example alkalimetal or alkaline earth metal nitrites, nitrous acid or concentratedred-brown nitric acid. This allows the required reaction temperature tobe reduced and the danger potential to be thereby further reduced.

[0044] The reactant of the general formula (II) may be metered into thenitric acid reaction mixture either as a melt or dissolved in a solvent.Useful solvents include liquids which are barely oxidizable if at alland are inert toward nitric acid under the given reaction conditions,preferably water, nitrobenzene, 1,2,4-trichlorobenzene or methylenechloride. Low-boiling solvents such as methylene chloride aretransported out of the reactor with the NO_(x) stream.

[0045] In the process according to the invention, preference is given tometering the compounds of the general formula (II) and in particular thenitrosulfonyltoluenes into the nitric acid as a 20-70%, preferably30-55%, aqueous solution.

[0046] DTA investigations of the reaction mixtures of the processaccording to the invention for oxidizing the nitro compounds of thegeneral formula (II) gave no grounds for any potential danger to safety;in the case of the present reaction mixtures, insignificant exothermicreactions only take place at temperatures in the range of 260-370° C.This is a significant advantage in terms of safety over the nearestprior art process having reverse operation, i.e. the initial chargingof, for example, 4-nitrotoluenesulfonic acid and subsequent metering inof nitric acid. DTA investigations of such reaction mixtures show thatthe first exothermic decomposition reactions commence at only 175° C.and that further decomposition proceeds above 250° C. to a quite massiveextent.

EXAMPLES Example 1 (Comparative)

[0047] In a 1 l tantalum autoclave equipped with a stirrer, refluxcondenser and a pressure-retaining valve set to 5 bar, 108.6 g ofwater-damp 4-nitrotoluene-2-sulfonic acid (0.39 mol) are suspended in120 g of water and heated to 140° C. A pressure of about 3.6 bar buildsup. Once this temperature is attained, 180 g of 70% by weight nitricacid are pumped into the autoclave within 5 h. Owing to the developmentof NO_(x), the pressure rises to the predetermined 5 bar, and when thispressure is exceeded, the nitrogen oxides formed are blown off. Afterthe end of the nitric acid metering, stirring is continued at 140° C.for 12 h. In the last hours of the continued stirring time, the pressurefalls again to below 5 bar and the offgas stream ceases. After theautoclave has been cooled to room temperature, it is depressurized andthe remaining nitrogen oxides are purged out using nitrogen. Theautoclave contents are transferred to a flask equipped with a stirrer,and 150 g of a cold saturated aqueous KCl solution are added. The4-nitro-2-sulfonylbenzoic acid precipitates as the potassium salt, isfiltered off, washed with cold water and dried in a drying cabinet.

[0048] 96 g of the monohydrate of the potassium salt of4-nitro-2-sulfonylbenzoic acid having a purity of 97% (HPLC) areisolated which corresponds to a yield of 78.5%, based on the4-nitrotoluene-2-sulfonic acid used.

[0049] In table 1, the reactant concentration in the reaction mixture ispresented as a function of the reaction time.

Example 2 (Comparative)

[0050] In the apparatus described in example 1, 108.6 g of water-damp4-nitrotoluene-2-sulfonic acid (0.39 mol) are suspended in 120 g ofwater and heated to 160° C. A pressure of about 6.1 bar builds up. Oncethis temperature is attained, 180 g of 70% by weight nitric acid arepumped into the autoclave within 4 h. Owing to the development ofNO_(x), the pressure rises to the predetermined 9 bar, and when thispressure is exceeded, the nitrogen oxides formed are blown off. Afterthe end of the nitric acid metering, stirring is continued at 160° C.for 1 h. In the last hours of the continued stirring time, the pressurefalls again to below 9 bar and the offgas stream ceases.

[0051] The work-up is effected in a similar manner to example 1, and92.4 g of the monohydrate of the potassium salt of4-nitro-2-sulfonylbenzoic acid having a purity of 97% (HPLC) areisolated which corresponds to a yield of 75.6%, based on the4-nitrotoluene-2-sulfonic acid used.

[0052] In table 1, the reaction concentration in the reaction mixture ispresented as a function of the reaction time.

Example 3

[0053] 581.5 g of 65% nitric acid are heated in a steel-enamel autoclaveto 160° C. 684.8 g of a 31.7% 4-nitrotoluene-2-sulfonic acid solutionare then metered in over 10 hours. The internal pressure is maintainedat 12 bar. Stirring is then continued at this temperature for 6 h. Thebatch is transferred with 150 g of water to a reservoir and 389.5 g of a50% potassium hydroxide solution are added dropwise at 60° C. over 2 h.After stirring for a further 2 hours, the batch is filtered. Theprecipitate is then washed twice with half of 150 g of ice-water eachtime. The product is dried at 50-80° C. and 50-100 mbar to obtain 273.8g, of product, of which 99.1% is the monopotassium salt of4-nitro-2-sulfonylbenzoic acid and 0.3% is the reactant, and the totalwater and potassium nitrate content is about 0.6%. The yield isaccordingly 94% of theory, based on the 4-nitrotoluene-2-sulfonic acidused.

[0054] In table 1, the reactant concentration in the reaction mixture ispresented as a function of the reaction time.

Example 4

[0055] 581.5 g of 65% nitric acid are heated in a steel-enamel autoclaveto 140° C. 684.8 g of a 31.7% 4-nitrotoluene-2-sulfonic acid solutionare then metered in over 10 hours. The internal pressure is maintainedat 12 bar. Stirring is then continued at this temperature for 6 h.

[0056] The work-up of the reaction mixture is effected as described inexample 3. A product is obtained which has a residual content of 2% ofthe potassium salt of 4-nitrotoluene-2-sulfonic acid. The yield of themonopotassium salt of 4-nitro-2-sulfonylbenzoic acid is about 91% oftheory, based on the 4-nitrotoluene-2-sulfonic acid used.

[0057] In table 1, the reactant concentration in the reactant mixture ispresented as a function of the reaction time. The slightly lowertemperature than in example 3 leads to steady state concentrations ofthe reactant of below 5% by weight. This value may be reduced by adding0.01 mol of sodium nitrite to the nitric acid before the reaction(example 5).

Example 5

[0058] 581.5 g of 65% nitric acid are admixed with 690 mg (0.01 mol) ofsodium nitrite and heated in a steel-enamel autoclave to 140° C. 684.8 gof a 31.7% 4-nitrotoluene-2-sulfonic acid solution are then metered inover 10 hours. The internal pressure is maintained at 12 bar. Stirringis then continued at this temperature for 6 h.

[0059] The work-up of the reaction mixture is effected as described inexample 3, and a product is obtained which still has a residual contentof 0.9% of the potassium salt of 4-nitrotoluene-2-sulfonic acid. Theyield of the monopotassium salt of 4-nitro-2-sulfonylbenzoic acid isabout 93% of theory, based on the 4-nitrotoluene-2-sulfonic acid used.

[0060] In table 1, the reactant concentration in the reaction mixture ispresented as a function of the reaction time. The steady stateconcentrations of the reactant during the reaction do not exceed 3% atany time. TABLE 1 Reactant concentration in the reaction mixture as afunction of the reaction time Reactant content in Time solution Example[hours] [% by weight] 1 (comparative) 0 37 2.5 13 5 5 17 0.7 2(comparative) 0 37 2 11 4 3 5 0.8 3 3.3 0.48 6.7 1.31 10 2.11 14 0.14 42 4.65 4 3.69 6 3 8 3.5 10 3.6 16 0.64 5 2 2.62 4 2.06 6 2.38 8 2.55 102.83 16 0.22

1. A process for preparing nitrobenzoic acids of the general formula (I)

where each X is independently nitro, cyano, sulfonyl, carboxyl,carbonylphenyl, trifluoromethyl or trichloromethyl, each Y isindependently phenyl, fluorine, chlorine, bromine or iodine and thephenyl radical may in turn be substituted by up to 3 X and/or Y radicalsother than hydrogen, m has the value 0, 1, 2 or 3 and n has the value 0,1, 2 or 3, and the sum of m and n has the value 0, 1, 2, 3 or 4, fromcompounds of the general formula (II)

where X, Y, m, n and also the sum of n and m are each as defined abovefor the general formula (I) and R is H or an OR′ radical and R′ is H,straight-chain or branched C₁-C₁₀-alkyl or straight-chain or branchedC₁-C₁₀-carbonylalkyl or R′ is a radical of the general formula (III)

 or a radical of the general formula (IV),

 where X, Y, n, m and also the sum of n and m are each as defined forthe general formula (I), characterized in that a mixture of nitric acidand water is heated at a pressure in the range of 2-20 bar attemperatures in the range of 100-220° C. and the compound of the generalformula (II) is metered into this heated mixture of nitric acid andwater, although compounds of the general formula (II) exclude2-halo-6-nitrobenzyl alcohols, esters or ethers of the general formula(V) and

 where R′ is as defined for the general formula (III), R¹, R² and R³ areeach independently H, fluorine, chlorine, bromine, nitro or carboxyl andHal is fluorine, chlorine or bromine.
 2. The process as claimed in claim1, characterized in that the maximum concentration of the compound ofthe general formula (II) in the reaction mixture is 7% by weight,preferably 6% by weight and in particular 5% by weight.
 3. The processas claimed in claim 1 or 2, characterized in that each X in the generalformulae (I) and (II) is independently a sulfonic acid or nitro radicaland each Y is independently fluorine or chlorine.
 4. The process asclaimed in one or more of claims 1-3, characterized in that n has thevalue 0, 1 or 2 and m has the value 0, 1 or 2, and the sum of n and mtakes the value 1 or
 2. 5. The process as claimed in one or more ofclaims 1-4, characterized in that a hydrogen atom or a fluorine atom,preferably a hydrogen atom, is in one of the o-positions to the group—CH₂R to be oxidized.
 6. The process as claimed in one or more of claims1-5, characterized in that the compound of the general formula (II) usedis a nitrotoluenesulfonic acid and in particular4-nitrotoluene-2-sulfonic acid.
 7. The process as claimed in one or moreof claims 1-6, characterized in that it is carried out at a pressure of4-15 bar, preferably of 6-12 bar and in particular of 10-12 bar and at atemperature of 120-200° C. and preferably of 140-180° C.
 8. The processas claimed in one or more of claims 1-7, characterized in that 10-90%,preferably 20-65%, nitric acid is initially charged.
 9. The process asclaimed in one or more of claims 1-8, characterized in that the molarratio of the compound of the general formula (II) to nitric acid is inthe range of (2-20):1 , preferably in the range of (3-10):1 and morepreferably in the range of (4-8):1.
 10. The process as claimed in one ormore of claims 1-9, characterized in that 10-90%, preferably 20-50%, ofthe nitric acid to be used is initially charged and heated, and then thecompound of the general formula (II) and the remaining nitric acid aremetered into the reactor simultaneously but separately.
 11. The processas claimed in one or more of claims 1-9, characterized in thatsubstances are added to the nitric acid which release or contain NO_(x),preferably alkali metal or alkaline earth metal nitrites, nitrous acidor concentrated red-brown nitric acid.